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Induction of Apoptosis by the Severe Acute Respiratory Syndrome Coronavirus 7a Protein Is Dependent on Its Interaction with the Bcl-X_L Protein

Ying-Xim Tan,^1, Timothy H. P. Tan,^1, Marvin J.-R. Lee,¹ Puay-Yoke Tham,¹ Vithiagaran Gunalan,¹ Julian Druce,² Chris Birch,² Mike Catton,² Nai Yang Fu,³ Victor C. Yu,³ and Yee-Joo Tan^1*

Collaborative Anti-Viral Research Group, Institute of Molecular and Cell Biology, Republic of Singapore,¹ Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria, Australia,² Mechanisms of Apoptosis in Mammalian Cells Group, Institute of Molecular and Cell Biology, Republic of Singapore³

Received 14 January 2007/ Accepted 23 March 2007

The severe acute respiratory syndrome coronavirus (SARS-CoV) 7a protein, which is not expressed by other known coronaviruses, can induce apoptosis in various cell lines. In this study, we show that the overexpression of Bcl-X_L, a prosurvival member of the Bcl-2 family, blocks 7a-induced apoptosis, suggesting that the mechanism for apoptosis induction by 7a is at the level of or upstream from the Bcl-2 family. Coimmunoprecipitation experiments showed that 7a interacts with Bcl-X_L and other prosurvival proteins (Bcl-2, Bcl-w, Mcl-1, and A1) but not with the proapoptotic proteins (Bax, Bak, Bad, and Bid). A good correlation between the abilities of 7a deletion mutants to induce apoptosis and to interact with Bcl-X_L was observed, suggesting that 7a triggers apoptosis by interfering directly with the prosurvival function of Bcl-X_L. Interestingly, amino acids 224 and 225 within the C-terminal transmembrane domain of Bcl-X_L are essential for the interaction with the 7a protein, although the BH3 domain of Bcl-X_L also contributes to this interaction. In addition, fractionation experiments showed that 7a colocalized with Bcl-X_L at the endoplasmic reticulum as well as the mitochondria, suggesting that they may form complexes in different membranous compartments.

Published ahead of print on 11 April 2007.

Y.-X.T. and T.H.P.T. contributed equally to this work.

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• Schaecher, S. R., Touchette, E., Schriewer, J., Buller, R. M., Pekosz, A. (2007). Severe Acute Respiratory Syndrome Coronavirus Gene 7 Products Contribute to Virus-Induced Apoptosis. J. Virol. 81: 11054-11068 [Abstract] [Full Text]